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Background: The aim is to measure the association between fibromyalgia syndrome (FMS) and post-traumatic stress disorder (PTSD), mood and anxiety disorders using reliable psychiatric diagnoses according to Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and with a case–control design. Methods: Case–control study with cases (71 consecutive female patients with FMS) and controls (284 subjects without FMS), randomly drawn after a gender- and age-matching technique from the database of an epidemiological survey. Psychiatric diagnoses were conducted according to DSM-IV and carried out by clinical staff using a structured interview (Advanced Neuropsychiatric Tools and Assessment Schedule). QoL was measured by Short Form Health Survey (SF-12). Results: The lifetime prevalence of major depressive disorder (MDD; 43.7% vs 8.1%, p < .0001), bipolar disorder (BD; 21.1% vs 0.7%, p  < .0001), PTSD (8.4% vs 1.4%, p < .0001) and panic disorder (28.2% vs 5.6%, p < .001) was higher in people with FMS than in controls. People with FMS showed a poorer QoL than controls on the SF-12 (26.43 ± 6.04 vs 37.45 ± 5.80, p < .0001). Those with comorbidity with MDD and BD showed a mean SF-12 score of 24.75 ± 6.31 versus 29.52 ± 4.84 ( N = 25) of people with FMS without any mood disorder ( p = .002). The attributable burden of FMS in worsening QoL was found comparable to that of serious chronic diseases such as multiple sclerosis. Conclusion: FMS is a disorder that 'in itself' can have a devastating impact on an individual's life. The frequency of the association with major depressive and bipolar disorders increases the impact on the QoL of people with FMS. One of the causes of this association appears to be the extreme vulnerability to chronic stress that this disorder involves. The findings have important clinical significance: the physician must interpret in the right dimension and with dignity the suffering of the people with FMS.